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ZZW-115–dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents
Wenjun Lan, … , José L. Neira, Juan Iovanna
Wenjun Lan, … , José L. Neira, Juan Iovanna
Published August 11, 2020
Citation Information: JCI Insight. 2020;5(18):e138117. https://doi.org/10.1172/jci.insight.138117.
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Research Article Cell biology Oncology

ZZW-115–dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

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Abstract

Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR.

Authors

Wenjun Lan, Patricia Santofimia-Castaño, Mirna Swayden, Yi Xia, Zhengwei Zhou, Stephane Audebert, Luc Camoin, Can Huang, Ling Peng, Ana Jiménez-Alesanco, Adrián Velázquez-Campoy, Olga Abián, Gwen Lomberk, Raul Urrutia, Bruno Rizzuti, Vincent Geli, Philippe Soubeyran, José L. Neira, Juan Iovanna

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Figure 2

NUPR1 interacted with importin-α3 in vitro.

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NUPR1 interacted with importin-α3 in vitro.
(A) Fluorescence spectrum of...
(A) Fluorescence spectrum of the complex formed by importin-α3 and NUPR1 (red) and that obtained by the addition of the spectra of both isolated biomolecules after excitation at 280 nm (blue). (B) Far-UV CD spectrum of the complex formed by importin-α3 and NUPR1 (red) and that obtained by the addition of the spectra of both isolated biomolecules (blue). (C and D) ITC raw data (top, thermal power [dQ/dt], as a function of time [t]) and titration curve or binding isotherm (bottom, ligand-normalized injection heats [Q], as a function of the reactants molar ratio) for the interaction between importin-α3 and NUPR1 in the absence (C) or presence (D) of ZZW-115. (E) PLA was performed in MiaPaCa-2 cells transfected with a plasmid expressing importin-α3–Flag in the presence or absence of ZZW-115 (5 μM) for 6 hours. Mouse anti-Flag and rabbit anti-NUPR1 antibodies were used. A representative experiment is shown (n = 3). ImageJ was used to count the number of red dots. Data represent mean ± SEM of 6 field, Student’s 2-tailed unpaired t test was used, **P < 0.01.

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